PROJECT SUMMARY The association between endplate pathology and chronic low back pain (cLBP) is widely acknowledged, but methods for identifying cLBP patients in whom endplate pathology is a contributing factor, for uncovering treatment targets, and for patient selection remain qualitative, subjective, and underdeveloped. The premise of this new project is that we can solidify pain mechanisms and improve patient selection by developing and translating new imaging tools, technologies and/or methods (iTTM) that provide accurate, noninvasive measures of endplate pathologies. Our search for clinically relevant biomarkers of endplate pathology will: 1) focus on novel imaging measures of endplate bone marrow lesion (BML) severity with IDEAL MRI and cartilage endplate (CEP) fibrosis/damage with UTE MRI; 2) assess interactions with paraspinal muscles; and 3) identify metrics that associate with pain, disability, and degeneration. In the UH2 phase, we will refine our imaging and post-processing methodologies by leveraging and expanding two existing cross-sectional cohorts. In the UH3 phase, we will be poised to deploy the new endplate iTTM to other BACPAC sites in order to prospectively test the most promising metrics' clinical utility in multi-site validation studies. Three complementary aims are proposed. In Aim 1 (UH2) we will further develop and validate quantitative MRI measures of BML severity and CEP fibrosis. By imaging cLBP patients with both new and legacy MRI sequences, we will determine if including measures of BML severity and/or CEP damage from new sequences significantly improves predictive models of pain compared to models with conventional BML presence/absence only, i.e. Modic changes. We will also discover metrics of CEP fibrosis that associate with the extent of disc degeneration in order to clarify mechanistic links between CEP composition, nutrient transport, and disc cell function. In Aim 2 (UH3) we will prospectively conduct multi-site, longitudinal observational studies of cLBP patients to test the relationship between these MRI measures of endplate pathology and subsequent changes in pain and spine health. Finally, in Aim 3 (UH3) we will test if our MRI measures of BML severity and CEP fibrosis predict treatment response. Current MRIs used to select cLBP patients for new, minimally invasive therapies lack the sophistication to delineate the best patients or levels to treat. Specifically, nerve ablation strategies for innervated endplate BML are unable to distinguish BML severity, and intradiscal biologic therapies for disc regeneration are unable to or identify candidates with adequate nutrient supply. By observing cLBP patients undergoing treatment with these promising non-addictive therapies, we will test if responder vs. non-responder status depends on BML severity or CEP fibrosis. Collectively, the results from these studies will provide validated iTTM that are useful for addressing the endplates' role in cLBP, identifying sub-phenotypes, discovering pain mechanisms, uncovering treatment targets, and selecting patients.